Muc2 Mucin and Nonmucin Microbiota Confer Distinct...

Muc2 Mucin and Nonmucin Microbiota Confer Distinct Innate Host Defense in Disease Susceptibility and Colonic Injury

Abstract

BACKGROUND & AIMS: Alterations in intestinal MUC2 mucin and microbial diversity are closely linked with important intestinal pathologies; however, their impact on each other and on intestinal pathogenesis has been vaguely characterized. Therefore, it was of interest in this study to delineate distinct and cooperative function of commensal microbiota and the Muc2 mucus barrier in maintaining intestinal epithelial barrier function. METHODS: Muc2 mucin deficient (Muc2^-/-) and sufficient (Muc2^+/+) littermates were used as a model for assessing the role of Muc2. To quantify the role of the microbiota in disease pathogenesis, Muc2^+/+ and Muc2^-/- littermates were treated with a cocktail of antibiotics that reduced indigenous bacteria, and then fecal transplanted with littermate stool and susceptibility to dextran sulphate sodium (DSS) quantified. RESULTS: Although, Muc2^+/+ and Muc2^-/- littermates share similar phyla distribution as evidenced by 16S sequencing they maintain their distinctive gastrointestinal phenotypes. Basally, Muc2^-/- showed low-grade colonic inflammation with high populations of inflammatory and tolerogenic immune cells that became comparable to Muc2^+/+ littermates following antibiotic treatment. Antibiotics treatment rendered Muc2^+/+ but not Muc2^-/- littermates highly susceptibility to DSS-induced colitis that was ILC3 dependent. Muc2^-/- microbiota was colitogenic to Muc2^+/+ as it worsened DSS-induced colitis. Microbiota dependent inflammation was confirmed by bone-marrow chimera studies, as Muc2^-/- receiving Muc2^+/+ bone marrow showed no difference in their susceptibility toward DSS induced colitis. Muc2^-/- microbiota exhibited presence of characteristic OTUs of specific bacterial populations that were transferrable to Muc2^+/+ littermates. CONCLUSIONS: These results highlight a distinct role for Muc2 mucin in maintenance of healthy microbiota critical in shaping innate host defenses to promote intestinal homeostasis.